Adolescence is a critical period for drug addiction in humans. Most life-long drug addiction is initiated during adolescence and several clinical studies suggest that the progression from initial drug use to compulsive drug-taking behaviors occurs faster during adolescence. The mission of this work is to identify the neural substrates that mediate adolescent vulnerability to substance abuse. This will enable the design of more successful preventative and therapeutic approaches to adolescent drug dependence. Forebrain dopamine systems mediate the rewarding and locomotor effects of psychostimulants. Work in this lab has found that a single high dose of cocaine induces more behavioral sensitization in adolescents. This finding suggests that stimulants may induce more neurobiological alterations that lead to exaggerated responsiveness to subsequent treatment in adolescents. This could provide a model for understanding why adolescents become addicted to drugs faster. The purpose of this study is to compare how a single high dose of cocaine alters dopamine responsiveness in adolescents and adults. Specifically, this study will investigate changes in dopamine neurotransmission, postsynaptic receptor sensitivity, and pre- and postsynaptic gene expression patterns. Adolescent and adult rats will be treated with saline or a high dose of cocaine (40 mg/kg) in locomotor test chambers. We will measure changes in dopamine transmission in vivo using fast scan cyclic voltammetry. The animals will be challenged with cocaine (10 mg/kg) 24 hours after the initial pretreatment and stimulated dopamine overflow will be analyzed. Postsynaptic dopamine receptor sensitivities will be measured in vitro using [35S] GTPyS assays on membrane preparations made from tissues collected from animals killed 24 hours after their initial pretreatment. Gene expression patterns will be measured using cDNA microarray analysis. Neurons containing dopamine D1 receptors will be dissected and total RNA will be extracted. The identification of specific ontogenetic differences in alterations of dopamine responsiveness could lead to new-targeted therapies for drug dependence and prevention during adolescence. Drug dependence is a significant health problem in this country and most people become addicted to drugs during adolescence. This research will try to understand how the adolescent brain responds differently to drugs than the adult brain. This knowledge could lead to better prevention and treatment of drug dependence in adolescents. [unreadable] [unreadable] [unreadable]